One-Electron Reduction of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin: A Pulse Radiolysis Study

Abstract

Geldanamycin, a benzoquinone ansamycin antibiotic, is a natural product inhibitor of Hsp90 with potent and broad anticancer properties but with unacceptable levels of hepatotoxicity. Consequently, numerous structural analogs, which differ only in their 17-substituent, have been synthesized including the water-soluble and less toxic 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, Alvespimycin). It has been suggested that the different hepatotoxicity reflects the redox active properties of the quinone moiety. The present pulse radiolysis study was aimed at studying the one-electron reduction of 17-DMAG. The UV-visible spectrum of the semiquinone radical, its pK(a), and the second-order rate constants for the reactions of 17-DMAG with CO(2)(•-) and (CH(3))(2)C(•)OH have been obtained. The reduction potential of 17-DMAG has been determined to be -194 ± 6 mV (vs NHE) using oxygen, 1,4-naphthoquinone, and menadione as electron acceptors. This reduction potential is lower than that of O(2) demonstrating that thermodynamically the semiquinone radical can reduce O(2) to superoxide, particularly since the concentration of O(2) is expected to exceed that of the drug in cells and tissues.